rs118203415
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Variant summary
Our verdict is Benign. Variant got -21 ACMG points: 0P and 21B. BP4_StrongBP6_Very_StrongBP7BS1BS2
The NM_000368.5(TSC1):āc.618T>Cā(p.His206=) variant causes a synonymous change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.0000533 in 1,614,210 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a benign outcome for this variant. Variant has been reported in ClinVar as Likely benign (ā ā ).
Frequency
Genomes: š 0.00012 ( 0 hom., cov: 32)
Exomes š: 0.000047 ( 0 hom. )
Consequence
TSC1
NM_000368.5 synonymous
NM_000368.5 synonymous
Scores
2
Clinical Significance
Conservation
PhyloP100: 2.76
Genes affected
TSC1 (HGNC:12362): (TSC complex subunit 1) This gene is a tumor suppressor gene that encodes the growth inhibitory protein hamartin. The encoded protein interacts with and stabilizes the GTPase activating protein tuberin. This hamartin-tuberin complex negatively regulates mammalian target of rapamycin complex 1 (mTORC1) signaling which is a major regulator of anabolic cell growth. This protein also functions as a co-chaperone for Hsp90 that inhibits its ATPase activity. This protein functions as a facilitator of Hsp90-mediated folding of kinase and non-kinase clients, including TSC2 and thereby preventing their ubiquitination and proteasomal degradation. Mutations in this gene have been associated with tuberous sclerosis and lymphangioleiomyomatosis. [provided by RefSeq, May 2022]
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ACMG classification
Classification made for transcript
Verdict is Benign. Variant got -21 ACMG points.
BP4
?
Computational evidence support a benign effect (BayesDel_noAF=-0.56).
BP6
?
Variant 9-132921864-A-G is Benign according to our data. Variant chr9-132921864-A-G is described in ClinVar as [Likely_benign]. Clinvar id is 49072.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr9-132921864-A-G is described in Lovd as [Benign].
BP7
?
Synonymous conserved (PhyloP=2.76 with no splicing effect.
BS1
?
Variant frequency is greater than expected in population eas. gnomad4 allele frequency = 0.000118 (18/152336) while in subpopulation EAS AF= 0.00289 (15/5186). AF 95% confidence interval is 0.00178. There are 0 homozygotes in gnomad4. There are 10 alleles in male gnomad4 subpopulation. Median coverage is 32. This position pass quality control queck.
BS2
?
High AC in GnomAd4 at 18 AD gene.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TSC1 | NM_000368.5 | c.618T>C | p.His206= | synonymous_variant | 7/23 | ENST00000298552.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TSC1 | ENST00000298552.9 | c.618T>C | p.His206= | synonymous_variant | 7/23 | 1 | NM_000368.5 | P4 |
Frequencies
GnomAD3 genomes ? AF: 0.000118 AC: 18AN: 152218Hom.: 0 Cov.: 32
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GnomAD3 exomes AF: 0.000203 AC: 51AN: 251306Hom.: 0 AF XY: 0.000199 AC XY: 27AN XY: 135810
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GnomAD4 exome AF: 0.0000465 AC: 68AN: 1461874Hom.: 0 Cov.: 32 AF XY: 0.0000468 AC XY: 34AN XY: 727242
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GnomAD4 genome ? AF: 0.000118 AC: 18AN: 152336Hom.: 0 Cov.: 32 AF XY: 0.000134 AC XY: 10AN XY: 74484
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ClinVar
Significance: Benign/Likely benign
Submissions summary: Benign:11Other:1
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Tuberous sclerosis 1 Benign:3
Benign, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Nov 07, 2021 | - - |
Benign, criteria provided, single submitter | clinical testing | KCCC/NGS Laboratory, Kuwait Cancer Control Center | Jul 07, 2023 | - - |
Benign, criteria provided, single submitter | clinical testing | Invitae | Feb 01, 2024 | - - |
Tuberous sclerosis syndrome Benign:2Other:1
Benign, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 11, 2024 | - - |
not provided, no classification provided | curation | Tuberous sclerosis database (TSC1) | - | - - |
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
not specified Benign:2
Benign, criteria provided, single submitter | clinical testing | GeneDx | May 16, 2013 | This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease. - |
Likely benign, criteria provided, single submitter | clinical testing | Eurofins Ntd Llc (ga) | Nov 20, 2015 | - - |
Hereditary cancer-predisposing syndrome Benign:2
Benign, criteria provided, single submitter | curation | Sema4, Sema4 | Feb 18, 2021 | - - |
Likely benign, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 27, 2016 | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. - |
not provided Benign:1
Benign, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Sep 12, 2019 | - - |
Isolated focal cortical dysplasia type II Benign:1
Likely benign, criteria provided, single submitter | clinical testing | Illumina Laboratory Services, Illumina | Jun 14, 2016 | - - |
Computational scores
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Name
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BayesDel_noAF
Benign
CADD
Benign
DANN
Benign
RBP_binding_hub_radar
RBP_regulation_power_radar
Splicing
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at